Innate/Adaptive Immune Interactions in Gut Inflammation

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DESCRIPTION, OVERALL (provided by applicant): Controlled or physiologic inflammation is the hallmark of the normal mucosa associated lymphoid tissue in the gut associated with a general tone (at least in the Gl tract) of suppression. The overall hypothesis guiding this program project grant is that this control requires both arms of the immune system, innate and adaptive, as well as components of the non-immune barrier, to develop a system of tight regulation, most likely an interactive one. A defect in any component of this network may result in inflammation. Thus our focus is on the distinct aspects of innate, adaptive and non-immune responses which contribute to the overall suppressed tone of the Gl tract and to define specific interactions between the various pathways. What may be central to this regulation is the role that one cell type, the IEC, plays in this process. In project 1 we address the role of innate immunity via activation of a subpopulations of T cells by non-classical class I molecules expressed by intestinal epithelial cells. Project 2 looks at the role of chemokines/chemokine receptors in promoting vs. regulating inflammation. Project 3 assesses the role of a novel serine/threonine kinase MAST205 in regulating IL12 transcription and resulting inflammation and finally project 4 takes a look at interferon regulated genes (resulting from IL12 activation) in mediating intestinal inflammation in a number of models of inflammatory bowel disease. A centerpiece for this grant is the pathology/.accessioning core which has developed a strategy to acquire and process intestinal tissues in an organized and timely fashion. The projects detailed in this proposal should allow us to define distinct regulatory pathways and determine the level of their interactions. It looks at inflammation as a total process and dissects out components that are critical to the normal functioning of the gut and the preservation of homeostasis in the host. By analyzing abnormalities in this process, which might occur in the setting of uncontrolled inflammation (IBD), we will have a better window in which to define normality. The result is the health of the host and new possibilities for therapeutic intervention in disease.